Neonatal cardiac dysfunction and transcriptome changes caused by the absence of Celf1

Abstract

The RNA binding protein Celf1 regulates alternative splicing in the nucleus and mRNA stability and translation in the cytoplasm. Celf1 is strongly down-regulated during mouse postnatal heart development. Its re-induction in adults induced severe heart failure and reversion to fetal splicing and gene expression patterns. However, the impact of Celf1 depletion on cardiac transcriptional and posttranscriptional dynamics in neonates has not been addressed. We found that homozygous Celf1 knock-out neonates exhibited cardiac dysfunction not observed in older homozygous animals, although homozygous mice are smaller than wild type littermates throughout development. RNA-sequencing of mRNA from homozygous neonatal hearts identified a network of cell cycle genes significantly up-regulated and down-regulation of ion transport and circadian genes. Cell cycle genes are enriched for Celf1 binding sites supporting a regulatory role in mRNA stability of these transcripts. We also identified a cardiac splicing network coordinated by Celf1 depletion. Target events contain multiple Celf1 binding sites and enrichment in GU-rich motifs. Identification of direct Celf1 targets will advance our knowledge in the mechanisms behind developmental networks regulated by Celf1 and diseases where Celf1 is mis-regulated.

CELF1 regulates gap junction integrity contributing to dilated cardiomyopathy

“…The RNA binding protein CUGBP, Elav-like family member 1 (CELF1 or CUGBP1) is involved in many different transcriptional and posttranscriptional regulatory systems that are important for both normal development and disease progression (6,16,17). CELF1 has been shown to regulate mRNA stability, polyadenylation status, and cytoplasmic translation of target transcripts (16).…”

“…CELF1 has been shown to regulate mRNA stability, polyadenylation status, and cytoplasmic translation of target transcripts (16). Interestingly, CEFL1 has been found to be relevant in a number of disease processes, including some cancers, myotonic dystrophy type 1, and heart disease (6,16,17). CELF1 is highly expressed in the developing myocardium with a strong nuclear presence and is an important RNA binding protein for fetal development (6,16,17).…”

“…Interestingly, CEFL1 has been found to be relevant in a number of disease processes, including some cancers, myotonic dystrophy type 1, and heart disease (6,16,17). CELF1 is highly expressed in the developing myocardium with a strong nuclear presence and is an important RNA binding protein for fetal development (6,16,17). CELF1 protein levels start to decrease 6–7 days after birth and are significantly decreased during adulthood (6,17).…”

“…CELF1 is highly expressed in the developing myocardium with a strong nuclear presence and is an important RNA binding protein for fetal development (6,16,17). CELF1 protein levels start to decrease 6–7 days after birth and are significantly decreased during adulthood (6,17). Protein kinase C (PKC) is responsible for the increased CELF1 levels during development, and mediates its downregulation in the adult heart through hyperphosphorylation (6).…”

“…Protein kinase C (PKC) is responsible for the increased CELF1 levels during development, and mediates its downregulation in the adult heart through hyperphosphorylation (6). When CELF1 was up-regulated in adult cardiomyocytes it led to arrhythmia, DCM, and eventual heart failure (6,17). Additionally, mouse models have shown that CELF1 over-expression in the heart results in splicing defects which leads to cardiomyopathy and ultimately cardiac failure (16,17).…”